Complete Protection against Pneumonic and Bubonic Plague after a Single Oral Vaccination

<div><p>Background</p><p>No efficient vaccine against plague is currently available. We previously showed that a genetically attenuated <i>Yersinia pseudotuberculosis</i> producing the <i>Yersinia pestis</i> F1 antigen was an efficient live oral vaccine against pneumonic plague. This candidate vaccine however failed to confer full protection against bubonic plague and did not produce F1 stably.</p><p>Methodology/Principal Findings</p><p>The <i>caf</i> operon encoding F1 was inserted into the chromosome of a genetically attenuated <i>Y</i>. <i>pseudotuberculosis</i>, yielding the VTnF1 strain, which stably produced the F1 capsule. Given orally to mice, VTnF1 persisted two weeks in the mouse gut and induced a high humoral response targeting both F1 and other <i>Y</i>. <i>pestis</i> antigens. The strong cellular response elicited was directed mostly against targets other than F1, but also against F1. It involved cells with a Th1—Th17 effector profile, producing IFNγ, IL-17, and IL-10. A single oral dose (10⁸ CFU) of VTnF1 conferred 100% protection against pneumonic plague using a high-dose challenge (3,300 LD₅₀) caused by the fully virulent <i>Y</i>. <i>pestis</i> CO92. Moreover, vaccination protected 100% of mice from bubonic plague caused by a challenge with 100 LD₅₀<i>Y</i>. <i>pestis</i> and 93% against a high-dose infection (10,000 LD₅₀). Protection involved fast-acting mechanisms controlling <i>Y</i>. <i>pestis</i> spread out of the injection site, and the protection provided was long-lasting, with 93% and 50% of mice surviving bubonic and pneumonic plague respectively, six months after vaccination. Vaccinated mice also survived bubonic and pneumonic plague caused by a high-dose of non-encapsulated (F1^-) <i>Y</i>. <i>pestis</i>.</p><p>Significance</p><p>VTnF1 is an easy-to-produce, genetically stable plague vaccine candidate, providing a highly efficient and long-lasting protection against both bubonic and pneumonic plague caused by wild type or un-encapsulated (F1-negative) <i>Y</i>. <i>pestis</i>. To our knowledge, VTnF1 is the only plague vaccine ever reported that could provide high and durable protection against the two forms of plague after a single oral administration.</p>